What is the significance of testosterone free and total testing in diagnosing and managing conditions related to abnormal testosterone levels?

From the Guidelines

Testosterone testing, both free and total, is essential for accurately diagnosing and managing testosterone-related disorders, with the most recent and highest quality study suggesting that total testosterone levels below 300 ng/dL, in combination with clinical symptoms, should prompt consideration of testosterone replacement therapy 1.

Significance of Testosterone Testing

Testosterone testing is crucial for diagnosing and managing conditions related to abnormal testosterone levels. Total testosterone measures all testosterone in the blood, while free testosterone measures only the unbound, biologically active portion. Both tests should be used together for comprehensive evaluation, as total testosterone alone can be misleading in conditions where binding proteins are abnormal.

Possible Results and Interpretation

Normal ranges for total testosterone in adult men are typically between 300-1000 ng/dL, and for free testosterone, between 5-21 ng/dL. Treatment decisions for testosterone replacement therapy should be based on both laboratory values and clinical symptoms. The American Urological Association recommends using a total testosterone level below 300 ng/dL as a reasonable cut-off in support of the diagnosis of low testosterone, with symptoms such as decreased energy, libido, muscle mass, and body hair, as well as hot flashes, gynecomastia, and infertility 1.

Clinical Considerations

For accurate results, blood should be drawn in the morning when levels are highest, and multiple measurements are recommended due to natural fluctuations. The diagnosis of testosterone deficiency requires both a low testosterone measurement and the presence of select symptoms and/or signs. Regular monitoring of both total and free testosterone during treatment helps optimize dosing and minimize side effects like erythrocytosis, sleep apnea, and prostate issues 1.

Treatment and Monitoring

Treatment with testosterone-replacement therapy should be considered when the morning free testosterone by equilibrium dialysis is frankly low on at least 2 separate assessments, and the hypogonadism workup has been completed to rule out an etiology of hypogonadism unrelated to obesity. The method of testosterone replacement should be individualized for each patient, with transdermal testosterone preparations suggested for most hypogonadal men due to their convenience and ability to produce normal serum testosterone concentrations 1.

From the FDA Drug Label

Testosterone in plasma is 98 percent bound to a specific testosterone-estradiol binding globulin, and about 2 percent is free. Generally, the amount of this sex-hormone binding globulin in the plasma will determine the distribution of testosterone between free and bound forms, and the free testosterone concentration will determine its half-life

The significance of testosterone free and total testing is to diagnose and manage conditions related to abnormal testosterone levels.

• Total testosterone measures the total amount of testosterone in the blood, including both free and bound testosterone.
• Free testosterone measures the amount of testosterone that is not bound to proteins in the blood and is available to enter cells and perform its functions. Possible results of these tests include:
• Low total testosterone: may indicate hypogonadism, a condition in which the testes do not produce enough testosterone.
• Low free testosterone: may indicate a decrease in the amount of testosterone available to the body, even if total testosterone levels are normal.
• High total testosterone: may indicate hypergonadism, a condition in which the testes produce too much testosterone.
• High free testosterone: may indicate an increase in the amount of testosterone available to the body, even if total testosterone levels are normal. These tests are used to diagnose and manage conditions such as primary hypogonadism and hypogonadotropic hypogonadism 2.

From the Research

Significance of Testosterone Free and Total Testing

• Testosterone free and total testing is significant in diagnosing and managing conditions related to abnormal testosterone levels, such as hypogonadism in men and polycystic ovary syndrome in women 3.
• The diagnosis of testosterone deficiency syndrome is based on clinical manifestations and documentation of low testosterone, and biochemical tests, including total and free testosterone determinations, are used to confirm the diagnosis 4.
• Accurate measurement of total and free testosterone levels is essential for making the diagnosis of androgen disorders, and total testosterone should ideally be measured in a fasting state in the morning using a reliable assay, such as liquid chromatography tandem mass spectrometry 5, 6.

Possible Results

• Total testosterone levels can vary substantially over time due to biologic factors, and a change of 52% is necessary between serial morning results to confirm a significant difference 4.
• Free testosterone levels should ideally be measured by equilibrium dialysis method, and reference ranges for total testosterone can be applied to laboratories that are certified by the HoST Program 5.
• Reference ranges for testosterone assays vary significantly among laboratories, and the ranges are predominantly defined by limited population studies of men with unknown medical and reproductive histories 7.
• The circulating concentrations of total and free testosterone vary substantially in people over time due to biologic factors as well as due to measurement variation, and accurate measurement of total and free testosterone is essential for making the diagnosis of androgen disorders 6.

Interpretation of Results

• The biological variation parameters of calculated bioavailable testosterone and calculated free testosterone confer no advantage over total testosterone, and marked individuality of serum testosterone is evident even in healthy men 4.
• The homeostatic set point of a patient could decrease by half and still be within the reference interval, and prospective establishment of an individual's baseline over repeated measurements or symptoms regardless of serum testosterone concentration should be used to guide clinical decisions 4.
• Free testosterone levels should be measured in men in whom alterations in binding protein concentrations are suspected or in whom total testosterone levels are only slightly above or slightly below the lower limit of the normal male range for testosterone 6.